Impact of Clinical and Subclinical Hypersensitivity to Asparaginase in Acute Lymphoblastic Leukemia

Abstract

Asparaginase is an essential element of acute lymphoblastic leukemia treatment. It depletes serum asparagine (an amino acid necessary for synthesis of cellular proteins), deprives leukemic blast cells of asparagine, and eventually results in cell death. To gain benefit from asparaginase, asparagine depletion must be ensured by giving intensive therapy and completing the full course of treatment. Three formulations of asparaginase exist; two are derived from Escherichia coli, a native form and pegylated form, and one is derived from Erwinia chrysanthemi (Erwinia asparaginase). Like many large proteins, asparaginases are immunogenic, and some patients develop antibodies to asparaginase. Antibodies may result in clinical hypersensitivity or subclinical hypersensitivity without symptoms, and both can result in a reduction in asparaginase activity and may affect therapeutic benefit. Clinical hypersensitivity is the most common reason for patients to stop asparaginase treatment. Subclinical hypersensitivity can only be identified by laboratory testing; therapeutic monitoring of asparaginase activity is used as a surrogate measure for asparagine depletion.

From the Children’s Oncology Group: Evidence-Based Recommendations for PEG-Asparaginase Nurse Monitoring, Hypersensitivity Reaction Management, and Patient/Family Education

“…Vital Signs and Observation During Administration. Four review articles addressed the importance of measuring vital signs and observing for hypersensitivity reaction signs and symptoms during PEG-asparaginase administration (Asselin & Fisher, 2014;Ruggiero et al, 2013;Shinnick et al, 2013;Zanotti & Markman, 2001). Asparaginase hypersensitivity may present as a local (intramuscular injection site) or more generalized reaction, and either can be life threatening if not identified in a timely manner (Asselin & Fisher, 2014;Zanotti & Markman, 2001).…”

“…Reaction Grading Tool. Three review articles recommend utilizing a validated tool to systematically classify hypersensitivity reactions (Asselin & Fisher, 2014;Shinnick et al, 2013;Wallace, 2013). The tool may be determined by institutional standards or be specific to the medication in question.…”

“…Reaction Prevention. Asparaginase therapy is a cornerstone of ALL treatment, and careful decision making is required when considering an asparaginase formulation change or discontinuation due to hypersensitivity reactions (Asselin & Fisher, 2014;Shinnick et al, 2013;Zanotti & Markman, 2001). Successful desensitization protocols of asparaginase dose escalation and/or slowed infusion rates have been reported, but this practice has not been rigorously studied (Zanotti & Markman, 2001).…”

“…Four review articles addressed the importance of measuring vital signs and observing for hypersensitivity reaction signs and symptoms during PEG-asparaginase administration (Asselin & Fisher, 2014; Ruggiero et al, 2013; Shinnick et al, 2013; Zanotti & Markman, 2001). Asparaginase hypersensitivity may present as a local (intramuscular injection site) or more generalized reaction, and either can be life threatening if not identified in a timely manner (Asselin & Fisher, 2014; Zanotti & Markman, 2001). Most hypersensitivity reactions occur within minutes of starting the infusion and symptoms may be general (lethargy, malaise, headache), dermatologic (pruritus, urticarial rash, flushing, angioedema), respiratory (dyspnea, wheezing, bronchospasm, stridor), gastrointestinal (abdominal pain, nausea/vomiting, diarrhea), or cardiovascular (hypotension, bradycardia; Kirkbright & Brown, 2012; Lieberman et al, 2015; Ruggiero et al, 2013).…”

“…Three forms of the drug have since been approved in the United States: native asparaginase (L-asparaginase, Elspar®) derived from Escheria coli; Erwinia asparaginase (Erwinase®) derived from Erwinia chrysanthemi ; and PEG-asparaginase (pegaspargase, Oncaspar®), a version of L-asparaginase with polyethylene glycol covalently conjugated to it. L-asparaginase is no longer commercially available in the United States (Bechwith, Wheeler, & Jensen, 2013), and PEG-asparaginase is now used for frontline ALL therapy, given its prolonged half-life and intravenous administration option (Asselin & Fisher, 2014). Because the bacterial macromolecules of E. coli and Erwinia chrysanthemi are not native to humans, B-cell lymphocytes can produce anti-asparaginase antibodies which in turn trigger hypersensitivity reactions with the first or subsequent dose of the agent (Muller et al, 2001; Shinnick, Browning, & Koontz, 2013).…”